Background and Purpose- There has been a recent sharp rise in opioid-related deaths in the United States. Intravenous opioid use can lead to infective endocarditis (IE) which can result in stroke. There are scant data on recent trends in this neurological complication of opioid abuse. We hypothesized that increasing opioid abuse has led to a higher incidence of stroke associated with IE and opioid use. Methods- We used the 1993 to 2015 releases of the National Inpatient Sample and validated International Classification of Diseases, Ninth Revision, Clinical Modification codes ( ICD-9-CM) to identify hospitalizations with the combination of opioid abuse, IE, and stroke (defined as ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage). Survey weights provided by the National Inpatient Sample were used to calculate nationally representative estimates and population estimates from the United States. Census data were used to calculate annual hospitalization rates per 10 million person-years. Joinpoint regression was used to assess trends. Results- From 1993 through 2015, there were 5283 hospitalizations with stroke associated with IE and opioid use. Across this period, the rate of such hospitalizations increased from 2.4 (95% CI, 0.5-4.3) to 18.8 (95% CI, 14.4-23.3) per 10 million US residents. Joinpoint regression detected 2 segments: no significant change in the hospitalization rate was apparent from 1993 to 2008 (annual percentage change, 1.9%; 95% CI, -2.2% to 6.1%), and then rates significantly increased from 2008 to 2015 (annual percentage change, 20.3%; 95% CI, 10.5%-30.9%), most dramatically in non-Hispanic white patients in the Northeastern and Southern United States. Conclusions- US hospitalization rates for stroke associated with IE and opioid use were stable for ≈2 decades but then sharply increased starting in 2008, coinciding with the emergence of the opioid epidemic.